8932 J . Org. Chem., Vol. 63, No. 24, 1998
Georg et al.
1H), 7.09 (d, J ) 9.4 Hz, 1H), 7.32-7.64 (m, 11H), 7.75 (d, J
) 7.8 Hz, 2H), 8.16 (d, J ) 7.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 4.3, 5.2, 6.4, 6.8, 8.8, 18.1, 22.9, 23.8, 25.4, 26.8, 35.5,
37.1, 40.9, 45.6, 55.6, 58.1, 69.7, 71.1, 74.7, 75.1, 76.3, 79.2,
80.7, 84.2, 126.3, 126.4, 126.9, 128.0, 128.7, 128.8, 129.0, 130.2,
131.8, 133.7, 133.9, 138.1, 142.2, 144.5, 166.9, 167.0, 170.1,
171.1, 194.1, 204.4; IR (neat) 3425, 1740, 1725, 1700, 1660
cm-1; FAB HRMS m/z calcd for C57H75NO13Si2 1038.4855 (M
J ) 7.8 Hz, 2H), 4.32 (d, J ) 8.3 Hz, 1H), 4.67 (m, 1H), 4.81
(br s, 1H), 5.01 (d, J ) 7.7 Hz, 1H), 5.11 (br s, 1H), 5.71 (d, J
) 6.8 Hz, 1H), 5.82 (br d, J ) 7.1 Hz, 1H), 6.14 (t, J ) 8.6 Hz,
1H), 7.28 (d, J ) 9.3 Hz, 1H), 7.35-7.66 (m, 11H), 7.78 (d, J
) 7.3 Hz, 2H), 8.14 (d, J ) 7.4 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 11.7, 13.1, 22.6, 26.3, 35.3, 35.8, 42.6, 45.4, 54.8, 59.9,
70.6, 72.5, 73.3, 75.0, 78.4, 80.7, 81.3, 84.7, 127.0, 127.1, 128.2,
128.6, 128.7, 128.9, 129.1, 130.1, 131.9, 132.8, 133.3, 133.7,
138.1, 166.8, 167.1, 170.2, 172.5, 208.3; IR (neat) 3420, 1715,
1640 cm-1; FAB HRMS m/z calcd for C45H49NO13 (M + 1)
+ 1), found 1038.4859; [R]20 -73° (c ) 0.24, CH2Cl2).
D
10-Dea cetyl-10-k etop a clita xel (21). To an ice-cooled
solution of 2′-TBS-10-deacetyl-7-TES-10-ketopaclitaxel (20, 50
mg, 0.048 mmol) in anhydrous pyridine (3 mL) was added HF‚
Py (10 drops), was added and the mixture was stirred at room
temperature for 3.5 h. After diluting with EtOAc (50 mL),
the solution was washed sequentially with a saturated NaH-
CO3 solution, water, and brine. Drying (Na2SO4), removal of
the solvent, and flash column chromatography (silica gel,
EtOAc/hexane ) 3:2 to 3:1) afforded the pure product as a
colorless solid, 28.5 mg (74%): mp 181-184 °C; 1H NMR (300
MHz, CDCl3) δ 1.27 (s, 3H), 1.29 (s, 3H), 1.76 (s, 3H), 1.81 (m,
1H), 1.89 (s, 3H), 2.40 (m, 1H), 2.41 (s, 3H), 2.57 (m, 1H), 3.64
(d, J ) 6.8 Hz, 1H), 3.69 (d, J ) 5.4 Hz, 1H, exch. with D2O),
4.04 (m, 1H), 4.22 and 4.35 (2d, J ) 8.6 Hz, 2H), 4.84 (dd, J )
2.5 and 5.2 Hz, 1H), 4.92 (d, J ) 7.9 Hz, 1H), 5.79 (dd, J ) 2.2
and 8.7 Hz, 1H), 5.84 (d, J ) 6.8 Hz, 1H), 6.24 (t, J ) 8.8 Hz,
1H), 7.02 (d, J ) 8.7 Hz, 1H), 7.38-7.69 (m, 11H), 7.75 (d, J
) 7.1 Hz, 2H), 8.17 (d, J ) 7.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 8.3, 14.1, 22.5, 23.8, 26.9, 35.5, 35.6, 40.8, 45.3, 55.1,
58.3, 68.7, 72.0, 73.0, 74.5, 76.1, 79.1, 80.6, 84.1, 127.0, 128.4,
128.7, 128.8, 128.9, 129.0, 130.2, 132.0, 133.5, 133.9, 137.8,
141.7, 146.6, 166.8, 167.2, 170.3, 172.6, 193.9, 206.1; IR (neat)
3420, 1725, 1710, 1695, 1645 cm-1; FAB HRMS m/z calcd for
812.3282, found 812.3299; [R]20 -56° (c ) 0.85, CHCl3).
D
2′-TBS-10-ep i-7-TES-p a clita xel (24). To an ice-cooled
solution of 2′-TBS-7-TES-10R-hydroxypaclitaxel (22, 65 mg,
0.063 mmol) and DMAP (70 mg, 0.6 mmol) in anhydrous
pyridine (4 mL) was added dropwise freshly distilled acetic
anhydride (0.5 mL), and the mixture was stirred at room
temperature for 1.5 h. The mixture was then poured into
EtOAc (50 mL), washed with water, saturated NaHCO3
solution, and brine, dried (Na2SO4), concentrated, and purified
by flash column chromatography (silica gel, EtOAc/hexane )
1:2) affording the product as a colorless solid, 54 mg (80%):
1
mp 127-132 °C; H NMR (300 MHz, CDCl3) δ -0.31 (s, 3H),
-0.02 (s, 3H), 0.60 (m, 6H), 0.79 (s, 9H), 0.95 (t, J ) 7.8 Hz,
9H), 1.25 (s, 6H), 1.69 (s, 3H), 1.87 (s, 3H), 2.0 (m, 2H), 2.16
(s, 3H), 2.45 (m, 2H), 2.57 (s, 3H), 4.08 (d, J ) 6.7 Hz, 1H),
4.26 and 4.32 (2d, J ) 8.3 Hz, 2H), 4.66 (d, J ) 1.8 Hz, 1H),
4.71 (dd, J ) 6.2 and 10.1 Hz, 1H), 4.95 (d, J ) 6.7 Hz, 1H),
5.75 (br d, J ) 6.9 Hz, 2H), 6.08 (s, 1H), 6.13 (t, J ) 8.3 Hz,
1H), 7.09 (d, J ) 8.8 Hz, 1H), 7.31-7.62 (m, 11H), 7.74 (d, J
) 7.2 Hz, 2H), 8.14 (d, J ) 7.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ -4.7, 5.7, 7.1, 10.5, 14.6, 21.2, 21.9, 23.5, 25.9, 27.0,
37.6, 43.7, 47.1, 56.0, 58.8, 71.8, 72.6, 75.4, 75.5, 76.9, 79.2,
81.6, 84.6, 126.8, 127.3, 128.3, 128.7, 129.1, 130.5, 130.6, 132.5,
133.9, 134.5, 138.3, 140.6, 167.4, 169.6, 172.0, 175.0, 204.8;
IR (neat) 3420 (br), 1720, 1660 cm1; FAB HRMS m/z calcd for
C
45H47NO13 810.3126 (M + 1), found 810.3115; [R]20 -66° (c
D
) 1.1, CHCl3).
2′-TBS-10-d ea cetyl-7-TES-10r-h yd r oxyp a clita xel (22).
A solution of 2′-TBS-10-deacetyl-7-TES-10-ketopaclitaxel (20,
80 mg, 0.077 mmol) in ethanol (95%, 8 mL) was treated with
NaBH4 (15 mg, 0.385 mmol), and the mixture was stirred at
room temperature for 45 min. The solution was diluted with
EtOAc (50 mL), washed with water and brine, dried over Na2-
SO4, concentrated under reduced pressure, and purified by
flash column chromatography (silica gel, EtOAc/hexane ) 1:2),
yielding the product as a colorless solid, 52 mg (65%); starting
C
59H79NO14Si2 (M + 1) 1082.5117, found 1082.5136.
10-Ep ip a clita xel (25). To an ice-cooled solution of 2′-TBS-
10-epi-7-TES-paclitaxel (24, 50 mg, 0.046 mmol) in anhydrous
pyridine (3 mL) was added HF‚Py (15 drops), and the mixture
was stirred at room temperature for 3.5 h. After diluting with
EtOAc (50 mL), the solution was washed sequentially with
saturated NaHCO3 solution, water, and brine. Drying (Na2-
SO4), removal of the solvent, and flash column chromatography
(silica gel, EtOAc/hexane ) 3:2 to 3:1) afforded the pure
product as a colorless solid, 31 mg (79%): mp 173-176 °C; 1H
NMR (300 MHz, CDCl3) δ 1.28 (s, 3H), 1.46 (s, 3H), 1.59 (s,
3H), 1.79 (s, 3H), 2.13 (m, 1H), 2.15 (s, 3H), 2.20 (m, 2H), 2.38
(s, 3H), 2.42 (m, 1H), 3.14 (d, J ) 7.1 Hz, 1H, exchangeable
with D2O), 3.56 (d, J ) 5.9 Hz, 1H), 4.16 (d, J ) 3.6 Hz, 1H,
exchangeable with D2O), 4.27 (d, J ) 8.4 Hz, 1H), 4.37 (d, J )
8.4 Hz, 1H), 4.57 (m, 1H), 5.05 (dd, J ) 3.03 and 6.18 Hz, 1H),
5.85 (dd, J ) 2.2 and 9.1 Hz, 1H), 5.98 (d, J ) 5.9 Hz, 1H),
6.10 (t, J ) 8.3 Hz, 1H), 6.15 (s, 1H), 7.21 (d, J ) 9.1 Hz, 1H),
7.34-7.85 (m, 11H), 7.79 (d, J ) 7.1 Hz, 2H), 8.14 (d, J ) 8.6
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 13.6, 14.8, 20.9, 22.5,
22.7, 25.9, 33.4, 35.8, 43.3, 45.5, 54.6, 58.4, 69.8, 71.6, 73.6,
74.7, 75.8, 78.2, 81.8, 85.9, 127.0, 128.1, 128.6, 128.7, 128.8,
128.9, 130.1, 130.9, 131.8, 133.7, 133.8, 138.1, 138.3, 166.7,
169.1, 170.8, 171.8, 202.8; IR (neat) 3430 (br), 1730 (br), 1645
cm-1; FAB HRMS m/z calcd for C47H51NO14 (M + 1) 854.3388,
1
material recovered ) 9 mg (11%): mp 158-161 °C; H NMR
(300 MHz, CDCl3) δ -0.28 (s, 3H), 0.02 (s, 3H), 0.64 (m, 6H),
0.82 (s, 9H), 0.99 (t, J ) 7.8 Hz, 9H), 1.11 (s, 3H), 1.25 (s, 3H),
1.69 (s, 3H), 2.0 (m, 2H), 2.14 (s, 3H), 2.51 (m, 1H), 2.61 (s,
3H), 2.66 (d, J ) 4.3 Hz, 1H, exch. with D2O), 4.25 (d, J ) 8.3
Hz, 1H), 4.30 (d, J ) 6.8 Hz, 1H), 4.35 (d, J ) 8.3 Hz, 1H),
4.68 (d, J ) 1.9 Hz, 1H), 4.89 (dd, J ) 6.5 and 11.0 Hz, 1H),
5.03 (br d, J ) 7.8 Hz, 1H), 5.16 (d, J ) 2.5 Hz, 1H), 5.69 (d,
J ) 6.8 Hz, 1H), 5.76 (br d, J ) 8.8 Hz, 1H), 6.27 (t, J ) 8.0
Hz, 1H), 7.13 (d, J ) 8.8 Hz, 1H), 7.32-7.64 (m, 11H), 7.77 (d,
J ) 7.1 Hz, 2H), 8.16 (d, J ) 7.0 Hz, 2H); 13C NMR (125 MHz)
CDCl3 δ 5.2, 5.3, 5.9, 6.8, 6.9, 11.2, 12.9, 18.1, 23.1, 25.5, 26.4,
35.8, 36.9, 42.6, 45.7, 53.6, 55.7, 60.1, 71.8, 72.3, 75.1, 75.3,
76.8, 78.7, 81.1, 82.6, 84.2, 126.4, 127.0, 127.8, 128.6, 128.7,
128.8, 129.2, 130.2, 131.7, 132.2, 132.8, 133.6, 134.1, 138.4,
167.0, 169.8, 169.9, 171.4, 206.2; IR (neat) 3430, 1725, 1660
cm-1; FAB HRMS m/z calcd for C57H77NO13Si2 (M + 1)
1040.5012, found 1040.5028; [R]20 -66° (c ) 0.47, CH2Cl2).
found 854.3393; [R]20 -20° (c ) 0.70, CHCl3).
D
D
10-Dea cet yl-10r-h yd r oxyp a clit a xel (23). To an ice-
cooled solution of 2′-TBS-10-deacetyl-7-TES-10R-hydroxypa-
clitaxel (22, 55 mg, 0.053 mmol) in anhydrous pyridine (3 mL),
HF‚Py (10 drops) was added, and the mixture was stirred at
room temperature for 3.5 h. After diluting with EtOAc (50
mL), the solution was washed sequentially with saturated
NaHCO3 solution, water, and brine. Drying (Na2SO4), removal
of the solvent, and flash column chromatography (silica gel,
EtOAc/hexane ) 3:2 to 3:1) afforded the pure product as a
2′-TBS-10-d ea cetyl-10-ep i-7-TES-9r-h yd r oxyp a clita x-
el (26). A solution of 2′-TBS-10-deacetyl-7-TES-10R-hydroxy-
paclitaxel (22, 65 mg, 0.063 mmol) in ethanol (95%, 8 mL) was
treated with NaBH4 (10 mg, 0.28 mmol), and the mixture was
stirred at room temperature for 2.5 h. The solution was then
diluted with EtOAc (50 mL) washed with water and brine,
dried over Na2SO4, concentrated, and purified by flash column
chromatography (silica gel, EtOAc/hexane ) 2:3), yielding the
product 26 as a colorless solid, 41 mg (63%): mp 148-150 °C;
1H NMR (300 MHz, CDCl3) δ -0.28 (s, 3H), 0.01 (s, 3H), 0.74
(m, 6H), 0.81 (s, 9H), 1.03 (t, J ) 7.8 Hz, 9H), 1.34 (s, 3H),
1.48 (s, 3H), 1.81 (s, 3H), 1.95 (m, 2H), 2.16 (s, 3H), 2.41 (m,
1H), 2.54 (s, 3H), 2.99 (br s, 1H, exch. with D2O), 3.50 (d, J )
5.5 Hz, 1H), 4.24 (m, 2H), 4.35 (d, J ) 8.3 Hz, 1H), 4.72 (d, J
1
colorless solid, 30 mg (70%): mp 188-192 °C; H NMR (300
MHz, CDCl3) δ 1.13 (s, 3H), 1.22 (s, 3H), 1.67 (s, 3H), 1.86 (m,
1H), 1.91 (s, 3H), 2.29 (m, 2H), 2.39 (s, 3H), 2.49 (m, 1H), 2.81
(br s, 1H, exchangeable with D2O), 4.01 (d, J ) 4.7 Hz, 1H,
exchangeable with D2O), 4.14 (d, J ) 6.8 Hz, 1H), 4.21 (br d,